The ORF8 protein of SARS-CoV-2 mediates immune evasion through down-regulating MHC-Ι

• Published in: Proceedings of the National Academy of Sciences - PNAS 2021-06, Vol.118 (23), p.1-12
• Main Authors: Zhang, Yiwen, Chen, Yingshi, Li, Yuzhuang, Huang, Feng, Luo, Baohong, Yuan, Yaochang, Xia, Baijin, Ma, Xiancai, Yang, Tao, Yu, Fei, Liu, Jun, Liu, Bingfeng, Song, Zheng, Chen, Jingliang, Yan, Shumei, Wu, Liyang, Pan, Ting, Zhang, Xu, Li, Rong, Huang, Wenjing, He, Xin, Xiao, Fei, Zhang, Junsong, Zhang, Hui
• Format: Article
• Language: English
• Subjects: Animals; Antigen Presentation; Antigens; Autophagy; Autophagy - genetics; Autophagy - immunology; Biological Sciences; Chlorocebus aethiops; Coronaviruses; COVID-19; COVID-19 - genetics; COVID-19 - immunology; Cytotoxicity; Down-Regulation - immunology; Gene sequencing; HEK293 Cells; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - immunology; Homology; Humans; Immune Evasion; Immunosurveillance; Lymphocytes; Lymphocytes T; Lysis; Lysosomes; Lysosomes - genetics; Lysosomes - immunology; Lysosomes - virology; Major histocompatibility complex; Mice; Mice, Transgenic; Pandemics; Phagocytosis; Proteins; SARS-CoV-2 - genetics; SARS-CoV-2 - immunology; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Vero Cells; Viral diseases; Viral Proteins - genetics; Viral Proteins - immunology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2024202118

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic and has claimed over 2 million lives worldwide. Although the genetic sequences of SARS-CoV and SARS-CoV-2 have high homology, the clinical and pathological characteristics of COVID-19 differ significantly from those of SARS. How and whether SARS-CoV-2 evades (cellular) immune surveillance requires further elucidation. In this study, we show that SARS-CoV-2 infection leads to major histocompability complex class Ι (MHC-Ι) down-regulation both in vitro and in vivo. The viral protein encoded by open reading frame 8 (ORF8) of SARS-CoV-2, which shares the least homology with SARS-CoV among all viral proteins, directly interacts with MHC-Ι molecules and mediates their down-regulation. In ORF8-expressing cells, MHC-Ι molecules are selectively targeted for lysosomal degradation via autophagy. Thus, SARS-CoV-2–infected cells are much less sensitive to lysis by cytotoxic T lymphocytes. Because ORF8 protein impairs the antigen presentation system, inhibition of ORF8 could be a strategy to improve immune surveillance.